Wagner-Régeny first gained notice as a composer with his theatre pieces for Essen. In 1929 he met the designer Caspar Neher, who wrote the texts for Wagner-Régeny's best-known operas. In 1930 Wagner-Régeny became a naturalized German citizen, and married, his wife being half-Jewish. Between 1930 and 1945 he worked as a freelance composer and teacher, and with the rise of the Nazis was promoted by a faction of the party as a composer of the future despite the stylistic closeness of his music to the proscribed Kurt Weill. He managed to gain the friendship and esteem of Baldur von Schirach and his works were performed by Karl Böhm and Herbert von Karajan. However, the success of his opera Der Günstling (after Georg Büchner, Dresden, February 20, 1935) was followed by doubts regarding his subsequent output, ending in a scandal with his opera Johanna Balk at the Vienna State Opera (April 4, 1941), which aroused the ire of Joseph Goebbels. As punishment, Wagner-Regény was drafted into the military in 1942 (or 1943), though he managed to secure a desk job in the army, and survived the war.

After the close of World War II, Rudolf Wagner-Régeny opted for East instead of West Germany. He was director of the Rostock Hochschule für Musik from 1947 to 1950. In 1950 he was appointed as a professor of composition at the (East) Berlin Hochschule für Musik and at the Academy of Arts. He continued to work there until illness prevented it in 1968.

As a composer, Wagner-Regény wrote numerous symphonic works and chamber works. He composed 12 operas of which Die Bürger von Calais (1936, libretto by Neher), Johanna Balk (1938), Das Bergwerk zu Falun (1958, after ETA Hoffmann) (cf. "The Mines of Falun") and Prometheus (1959) are considered his best work. His 1958 balletTristan is also greatly admired. He struggled to find a musical language distinct from the extremes of modernism but without any association with fascist aesthetics. His early compositions were inspired by Busoni, Kurt Weill and Schoenberg. His theatre collaborations with Neher and Bertolt Brecht were also of importance for the development of his style. After composing works along traditional lines, he adopted his own twelve-tone serial technique in 1950. In their transparency and austerity, his stage works follow the music theatre of Weill and Hanns Eisler and somewhat parallel those of Boris Blacher.